Cardiac biomarkers

ESR

Physiology

• Erythrocyte sedimentation rate; the rate at which EDTA-treated diluted RBCs clump together in a vertical test tube.
• Elevated in inflammatory conditions, mainly because of the increased amount of fibrinogen, which is an acute phase reactant.
• Myocardial infarction and myocardial necrosis cause an elevated ESR, more so than mere angina pectoris (Riseman and Brown, 1937)

Advantages:

• Easy to perform.
• Requires no special equipment, and minimal technical skill
• Uses widely available cheap reagents.
• Available in resource-poor environments.

Disadvantages:

• Takes about one hour to perform
• Completely non-specific.
• Old-school: as sophistication of laboratories has increased, the demand for ESR testing has diminished
• Varies with age, temperature, test tube position... Unreliable
• Non-cardiac causes of elevation:
  • Sepsis
  • Malignancy (eg. multiple myeloma)
  • Inflammatory disease, eg. RA/PMR
  • Chronic renal failure
  • Vasculitis, eg. temporal arteritis

CRP

Physiology

• C-reactive protein is the protein responsible for precipitating C-polysaccharide during the acute phase of Streptococcus pneumonia infection.
• Produced by the liver
• Its role is as an opsonin; it binds to soluble or particulate ligands and activates complement. Macrophages also have CRP receptors.
• It rises on the second day following an MI, and peaks on the fourth day (Levinger et al, 1957)

Advantages:

• Cheap
• Easy to perform
• Widely available
• Peaks late; it can therefore be used to detect an infarction which has occurrsed many days ago (in contrast to CK MB, which is gone within two days).
• As a part of a package of tests, it may improve the predictive value of risk analysis tools (Ridker et al, 1998)
• Angina alone will not cause an elevation of CRP (de Beer et al, 1982)

Disadvantages:

• A nonspecific marker of inflammation
• Non-cardiac causes of elevation:
  • Surgery, trauma
  • Burns
  • Sepsis
  • Rheumatological disease
• Unreliable in patients with a dysfunctional liver

AST

Physiology

• Aspartate aminotransferase (AST), formerly SGOT (serum glutamic oxaloacetic transaminase) is a 45 kD protein which is released from necrotic tissue.
• High concentrations are present in liver, kidney, skeletal muscle and myocardium.
• AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate. Vitamin B6 is required as a co-factor for this process.

Advantages:

• Rises up to 20 times the normal level within 48 hours of an MI (LaDue, 1957)
• Starts going up about 8 hours after the onset of chest pain
• Does not rise with angina (only MI)
• Does not rise with inflammatory states, and is therefore better than ESR or CRP.

Disadvantages:

• Also present in red blood cells: haemolysis will lead to spurious elevation
• Not cardio-specific
• Does not rise unless myocardial necrosis has occurred (Dewar et al, 1959)

CK

Physiology

• CK (creatine kinase) is the enzyme which catalyses the conversion of creatine into  phosphocreatine using one molecule of ATP. This reversible reaction can then be used to create ATP out of phosphocreatine and ADP.
• All muscle tissue is rich in CK, but all cells possess some CK, particularly specialised tissues such as retina, pancreas, placenta, the intestinal brush border, and many others (Wallimann and Hemmer, 1994)

Advantages:

• Does not rise unless there has been myocardial damage. Normal levels were always found in patients with congestive heart failure, rapid supraventricular arrhythmias, and acute coronary insufficiency without evidence of infarction (Vincent et al, 1965)
• Rapidly increasing levels: rises before AST, and peaks 15-20 hours post infarction.
• Usually normal in sepsis, malignancy and renal failure.

Disadvantages:

• Early peak and rapid clearance do not permit diagnosis in a delayed presentation of MI
• Not specific for the myocardium: released from any infarcted or damaged muscle

LDH

Physiology

• Lactate dehydrogenase catalyzes the conversion of lactate to pyruvate, and back from pyruvate into lactate. It is one of the most ancient enzymes, with all animals and plants having some version of it.
• There are numerous isoenzymes, and they are not completely tissue-specific. Howeve, LDH₁ is apparently very specific for the heart

Advantages:

• Elevated early: usually already raised in the first blood sample taken from the patient.
• Sensitivity of LDH₁ in myocardial infarction exceeds 95% (Sobel et al, 1972)

Disadvantages:

• It is rare to find a laboratory which will do LDH isoenzymes.
• LDH isonezyme assays frequently disagree between themselves.
• Rapid drop in levels prevents delayed diagnosis
• Total LDH (without isoenzyme breakdown) is highly non-specific.
• In patients with haemolysis due to artifical valves, LDH is chronically elevated
• LDH may become elevated in tachycardias and other non-ischaemic states of cardiac strain

CK-MB

Physiology:

• The myocardium-specific isoenzyme of CK.
• Released into the circulation along with other CK isoforms during a myocardial infarction

Advantages:

• Before there were serial troponins, there was CK-MB. It was used in the 1990s as a highly specific (not low-sensitivity) test for MI (Gibler et al, 1990)
• Sensitivity improved in mid-1990s until rapid assays achieved 95.7% sensitivity and 963.9% specificity  (Puleo et al, 1994)

Disadvantages:

• The older assays for CK-MB may have some cross-reactivity with other isoforms, generating false positives -eg. when measuring CK-MB and Ck-BB in combination (Tseng, 1981)
• The sensitivity and specificity is still lower than that of the troponin.
• Since this has ben superseded by troponin, its availability has declined to virtually zero.

Myoglobin

Physiology:

• Non-specific muscle protein, released during any even causing muscle damage
• Myocardial infarction with ensuing necrosis results in myoglobin leak.
• The myoglobin can rise before CK-MB or total CK: at "zero hour" (i.e. on presentation) the myoglobin is raised in about 50% of patients, whereas the other markers you had to wait for (Gibler et al, 1987)

Advantages:

• Early sensitivity of myoglobin in patients presenting within 4 hours is quite good, apparently equivalent to the early troponin assays (Mair et al, 1995)

Disadvantages:

• Poor specificity for the myocardium: wil be elevated in numerous disease states
• In the ICU, all manner of non-cardiac illnesses and interventions will result in a raised myoglobin
• Early peak (4 hours following  chest pain) doe snot permit delayed diagnosis
• If troponin is available, there is no advantage to the use of myoglobin (as troponin also allows early detection, and is more myocardium-sensitive)

Troponin-T and Troponin-I

Physiology:

• Troponin is an enzyme involved in the excitation-contraction coupling of the myocardium.
• Troponin T serves to attach the troponin complex to actin and tropomyosin.
• Myocardiac damage (for example infarction) causes the release of troponin.
• There is a cytosolic pool (which is released early in the infarct) and a structural pool (which is slowly released over days as the damaged myocardium decomposes).

Advantages:

• Its a sensitive and specific marker of myocardial ischaemia.
• It is more sensitive and specific than AST, CK and CK-MB (which are also found is skeletal muscle)
• It is an independent predictor of 30-day mortality in STEMI 
• It is associated with a poorer outcome in the critically ill patients.
• Troponin levels can be used to monitor for myocardial ischaemia in critically ill patients when history and examination are unreliable.

Disadvantages:

• A reliance on biomarkers may become unhealthy if it takes focus off clinical examination and history.
• It is not quantitatively validated outside the setting of ACS / AMI, but only qualitatively: i.e. a "positive" troponin is associated with worse outcomes in noncardiac critical illness, but we don't know whether a higher troponin is associated with a proportionally higher mortality.
• Troponin levels can be raised for a variety of non-cardiac reasons:
  • Myocardial ischaemia
  • Renal failure
  • Sepsis
  • Atrial fibrillation
  • Post-cardioversion
  • Cardiac trauma
  • Pulmonary embolism
  • Acute stroke or intracranial haemorrhage
  • Severe burns

Copeptin

Physiology:

• Copeptin is also known as C-terminal provasopressin.
• It is a 39-amino acid glycopeptide of unknown function in the circulation
• Copeptin is derived from a larger precursor peptide (preprovasopressin) along with  neurophysin II and vasopressin.

Advantages:

• May predict adverse outcome (measured at 3-5 days) according to the LAMP study (Khan et al, 2007)
• May be able to rapidly rule out AMI in the ED (Reichlin et al, 2009)

Disadvantages:

• Not specific for the myocardium. In fact, its whorishly indiscriminate. Recently people have been trying to promote copeptin as a biomarker in all sorts of other illnesses, such as sepsis, stroke, pancreatitis, and so forth (Reinstadler et al, 2015)
• The positive predictive value of copeptin used alone  as a diagnostic confirmation of  MI is "unacceptably low" according to a recent meta-analysis (Raskalova et al, 2014)

H-FABP

Physiology:

• Human-type Cytoplasmic Fatty Acid Binding Protein is a low molecular weight protein present in the myocardium.
• It is released early in AMI, and has been proposed as a biomarker of early myocardial injury.

Advantages:

• More sensitive and CK-BM and myoglobin (Okamoto et al, 2000)

Disadvantages:

• Not specific for MI - also elevated in sepsis (Reys et al, 2015)
• In primary care, H-FABP alone cannot be used to exclude MI (Bruins Slot et al, 2012)

BNP

Physiology:

• BNP (brain natriuretic peptide) is a 32-amino acid peptide released by the human atria and ventricles in response to distending pressure. In spite of its name, its presence in the human brain is rather minimal- it was first identified in porcine brain tissue, where for some reason it is concentrated. BNP is a peptide which has natriuretic and diuretic actions in the renal tubule, and is though to be a part of the natural homeostatic mechanisms which work in defence of normal intravascular volume.
• Thus, a raised BNP, suggesting increased atrial stretch, may be a serum marker which may differentiate cardiac failure and pulmonary oedema from respiratory infection in situations when both are equally likely on the basis of history and examination.

Advantages:

• BNP is promoted by the college answer as if it helps emergency physicians identify heart failure, but actual emergency physicians and clinical trial evidence disagree with this statement.
• It may also be a useful serum marker to guide the management of heart failure

• Disadvantages:
• There is no strong evidence supporting the use of BNP in discriminating between cardiac and non-cardiac causes of respiratory failure in critically ill patients.
• Though a 2007 study promoted BNP as a useful way to discriminate between cardiogenic pulmonary oedema and ARDS (its elevated in ARDS, but even more elevated in APO), a later 2008 study (Yardan et al) determined that its sensitivity is poor
• BNP is also elevated in sepsis, acute lung injury of any cause, pulmonary embolism, and after cardiac surgery.